Summary. Vascular disease is a common contributor to dementia, occurring in up to 40% of dementia cases, and is particularly common in patients with Alzheimer's disease (AD). It is also well established that vascular risk factors, such as hypertension, high LDL cholesterol, and type 2 diabetes, are risk factors for Alzheimer's dementia. More recently, specific vascular risk factors have been linked to cerebral spinal fluid-based biological markers of AD, even among cognitively normal adults. These findings could suggest that vascular risk factors could play an important role in the earliest stages of AD, which is thought to begin as much as 25 years prior to the onset of clinically significant symptoms. It has been hypothesized that vascular injury may precede and precipitate the development of neurodegeneration in AD due to blood-brain-barrier dysfunction and reduced cerebral blood flow, leading to brain leakage of neurotoxic blood products and chronic deprivation of oxygen and nutrient supply. Thus, vascular risk factors may be influencing the onset and course of AD through their effects on brain vascular function. The current proposal seeks to further examine this hypothesis by investigating whether cerebral spinal fluid- and magnetic resonance imaging-based measures of blood- brain-barrier damage and cerebral blood flow exhibit abnormalities during the earliest stages of cognitive decline in those with varying degrees of vascular risk, and whether these changes predict future decline and development of neuronal injury and structural brain changes consistent with AD. The proposed study will employ novel measures of cerebral spinal fluid proteins allowing for comprehensive investigation of brain vascular and neuronal function, as well as innovative magnetic resonance imaging technologies capable of identifying brain regions exhibiting increased blood-brain-barrier permeability and reduced cerebral blood flow. The application of these cutting-edge methods to the investigation of early vascular injury in those exhibiting vascular risk factors will provide unique insights into the earliest stages of AD, a time when preventative efforts are most likely to have an impact. Findings are likely to have major implications for early identification of vulnerable patient subgroups for prevention trials since vascular risk factors are often amenable to treatment.